Comparative hospitalization risk for SARS‐CoV‐2 Omicron and Delta variant infections, by variant predominance periods and patient‐level sequencing results, New York City, August 2021–January 2022

Abstract Background Comparing disease severity between SARS‐CoV‐2 variants among populations with varied vaccination and infection histories can help characterize emerging variants and support healthcare system preparedness. Methods We compared COVID‐19 hospitalization risk among New York City residents with positive laboratory‐based SARS‐CoV‐2 tests when ≥98% of sequencing results were Delta (August–November 2021) or Omicron (BA.1 and sublineages, January 2022). A secondary analysis defined variant exposure using patient‐level sequencing results during July 2021–January 2022, comprising 1–18% of weekly confirmed cases. Results Hospitalization risk was lower among patients testing positive when Omicron (16,025/488,053, 3.3%) than when Delta predominated (8268/158,799, 5.2%). In multivariable analysis adjusting for demographic characteristics and prior diagnosis and vaccination status, patients testing positive when Omicron predominated, compared with Delta, had 0.72 (95% CI: 0.63, 0.82) times the hospitalization risk. In a secondary analysis of patients with sequencing results, hospitalization risk was similar among patients infected with Omicron (2042/29,866, 6.8%), compared with Delta (1780/25,272, 7.0%), and higher among the subset who received two mRNA vaccine doses (adjusted relative risk 1.64; 95% CI: 1.44, 1.87). Conclusions Hospitalization risk was lower among patients testing positive when Omicron predominated, compared with Delta. This finding persisted after adjusting for prior diagnosis and vaccination status, suggesting intrinsic virologic properties, not population‐based immunity, explained the lower severity. Secondary analyses demonstrated collider bias from the sequencing sampling frame changing over time in ways associated with disease severity. Representative data collection is necessary to avoid bias when comparing disease severity between previously dominant and newly emerging variants.


| INTRODUCTION
Omicron (B.1.1.529 and BA lineages), a SARS-CoV-2 variant of concern, has caused less severe disease than prior variants in South Africa, 1,2 Europe, [3][4][5][6][7][8] and Canada. 9 Similar findings have been reported in the United States, based on national surveillance data and a large healthcare database, 10 healthcare systems, [11][12][13][14] and hospitals. 15,16 A limited number of studies to assess Omicron severity used population-based surveillance data linked to immunization registry data in the United States 17,18 or used patient-level whole-genome sequencing (WGS) results. 12,13,18,19 Diminished disease severity could result from Omicron's intrinsic virologic properties (e.g., lower replication competence in human lungs 20 21 By the time Omicron was introduced into NYC, substantial percentages of the population had been previously infected (a quarter of NYC residents were estimated to have been infected by mid-2020 before vaccine availability) 22,23 and vaccinated (72% completed the primary vaccine series and 21% had received an additional dose as of December 18, 2021). 24 During December 12, 2021-January 29, 2022, a total of 1,047,428 confirmed and probable cases of COVID-19 were diagnosed among NYC residents. 25 Given this surge in infections, we sought to leverage population-based surveillance, WGS, and immunization registry data to compare disease severity between Omicron and Delta infections, accounting for prior vaccination and diagnosis history.

| Infection with Delta and Omicron variants
Clinical and commercial laboratories are required to report SARS-  Figure 1). With the operational benefit of requiring only one dose, this vaccine had been differentially administered to certain populations, for example, homebound seniors. 31 These vaccine recipients likely disproportionately had underlying conditions associated with COVID-19 hospitalization and death; including them without accounting for these unobserved confounders could have biased results.

| Hospitalization and death
COVID-19 hospitalizations and deaths are ascertained by importing and matching data from supplemental systems. 32 Supplemental hospitalization data were obtained from emergency department syndromic surveillance, regional health information organizations, public hospitals, DOHMH's electronic death registry system, and hospitals' electronic health record systems. 32 These systems do not capture all hospitalizations, and although all systems capture fact of hospitalization, the underlying cause is not necessarily available. Thus, people hospitalized because of COVID-19 illness could not be distinguished from people hospitalized because SARS-CoV-2 infection exacerbated an underlying condition or because SARS-CoV-2 infection was an incidental diagnosis. 33 Incidental diagnoses were likely disproportionately common while Omicron predominated, given high infection prevalence. 34 COVID-19 hospitalizations were defined as NYC residents whose positive SARS-CoV-2 test was within 14 days before or 3 days after hospital admission. COVID-19 deaths were defined as NYC residents with a positive SARS-CoV-2 test, and (a) the cause-of-death on the death certificate was COVID-19 or similar; or (b) COVID-19 was not a cause-of-death on the death certificate but the patient died within 30 days of COVID-19 diagnosis, and the death was not attributable to external causes, such as injury. 32 Sensitivity analyses applied more specific definitions. For a more specific hospitalization definition, we restricted to the subset of COVID-19 hospitalizations for which, based on syndromic surveillance, patients had presented to the emergency department with COVID-19-like illness within +/À 14 days of diagnosis. COVID-19-like illness was defined as chief complaint or ICD-10 codes for pneumonia or influenza-like illness (i.e., fever, cough, sore throat, and/or respiratory illness) and without regard to the COVID-19 ICD-10 code. For a more specific deaths definition, we restricted to the subset with COVID-19 indicated on the death certificate.

| Vaccination status
By matching with NYC's Citywide Immunization Registry, patients were assigned a vaccination status indicating the number of valid recorded doses (0-3) of an mRNA vaccine (BNT162b2 from Pfizer-BioNTech or mRNA-1273 from Moderna) received ≥14 days before COVID-19 diagnosis. 35 We restricted third doses to those administered starting August 13, 2021, when the Advisory Committee on Immunization Practices recommended an additional dose after an initial series for eligible immunocompromised persons. 36 Doses administered outside of New York State and by federal entities might have been missed, reducing the number of doses ascertained per patient.
F I G U R E 1 Eligibility for analysis of New York City residents testing positive for SARS-CoV-2 infection during periods of Omicron or Delta variant predominance.

| Diagnosis history
Prior COVID-19 diagnosis was defined as a positive laboratory-based molecular or antigen test >90 days before diagnosis with Delta or Omicron infection. Repeat positive tests are considered possible reinfections after 90 days, per the surveillance case definition. 37 Prior diagnoses would have been missed among patients who resided outside of NYC when tested previously or who did not access testing, for instance during spring 2020 when testing availability was limited. 32

| Statistical analysis
The exposure of interest was infection with the Omicron or Delta variant, and the outcomes were hospitalization or death. Crude and adjusted relative risks (aRRs) and 95% confidence intervals (CIs) were calculated using Poisson regression with robust error variance. 38 Models adjusted for gender, age group (for hospitalizations: in   (Table 1). Patients testing positive during Omicron predominance were more likely to have been vaccinated with 1, 2, and 3 doses than patients testing positive during Delta predominance (Table 1), which was expected because the Omicron wave occurred after the Delta wave, allowing more time for vaccine administration.
Because limited temporal overlap was observed between the Delta wave and third vaccine dose administrations, 24  Missingness for covariates included in regression analyses was negligible (≤1.5%), except variables depending on geocoding (i.e., congregate setting residence and neighborhood poverty level) had up to 6.1% missingness (Table 1). We conducted regression modeling using complete case analysis, assuming data were missing completely at random.   (Figure 2, Table S2). The point estimate for deaths among patients infected with Omicron compared with Delta was similar to that of hospitalizations but with wider uncertainty (aRR 0.81; 95% CI: 0.58, 1.13) (Figure 2, Table S3). In sensitivity analyses using more specific outcome definitions with sparser observations (Figure 1 (Table S2).

| Hospitalization and death
Results were not robust in secondary analyses restricting to patients with sequencing results ( Figure S1). Of 29 866 NYC residents with Omicron sequencing results, 2042 (6.8%) were hospitalized and 446 (1.5%) died (Table S1)

DATA AVAILABILITY STATEMENT
Line-level data are not publicly available in accordance with patient confidentiality and privacy laws. Publicly available data are available from https://www1.nyc.gov/site/doh/covid/covid-19-data.page.